Progressive resistance exercise training and changes in resting-state functional connectivity of the caudate in persons with multiple sclerosis and severe fatigue: A proof-of-concept study.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS). While progressive resistance training (PRT) has been shown to reduce fatigue in persons with MS, it is not clear why these reductions occur. One hypothesis is that PRT may induce functional changes to the caudate, a region highly implicated in MS fatigue. The aim of the current study was to study the effects of PRT on overall fatigue impact and resting-state functional connectivity of the caudate in persons with MS reporting severe fatigue. Participants were semi-randomly assigned to either a 16-week home-based PRT (n = 5) or stretching control (n = 5) condition. Both groups demonstrated reductions in overall fatigue impact (main effect of time: F = .84, d = .65). Significant group × time interactions were found, with the PRT group demonstrating post-training increases in functional connectivity between the caudate and left inferior parietal (F = 66.0, p < .001), bilateral frontal (both p < .001), and right insula (F = 21.8, p = .002) regions compared to the stretching group. Furthermore, greater post-training increases in functional connectivity between the caudate and left inferior parietal region were associated with greater decreases in cognitive fatigue (r = -.52) specifically. This study provides initial evidence for the caudate as a potential neural substrate for the beneficial effects of PRT on fatigue in persons with MS.

Enhanced Recruitment During Executive Control Processing in Cognitively Preserved Patients With Pediatric-Onset MS.

OBJECTIVES: Youth and young adults with pediatric-onset multiple sclerosis (MS) are vulnerable to executive dysfunction; however, some patients do not demonstrate functional deficits despite showing abnormalities on structural magnetic resonance imaging (MRI). Cognitively intact adults with MS have shown enhanced activation patterns relative to healthy controls on working memory tasks. We aim to evaluate whether cognitively preserved pediatric-onset MS patients engage compensatory recruitment strategies to facilitate age-normative performance on a task of working memory. METHODS: Twenty cognitively preserved patients (mean age=18.7±2.7 years; 15 female) and 20 age- and sex-matched controls (mean age=18.5±2.9 years; 15 female) underwent neuropsychological testing and 3.0 Tesla MRI, including structural and functional acquisitions. Patterns of activation during the Alphaspan task, a working memory paradigm with two levels of executive control demand, were examined via whole-brain and region of interest (ROI) analyses. RESULTS: Across all participants, lower accuracy and greater activation of regions implicated in working memory were observed during the high demand condition. MS patients demonstrated 0.21 s longer response time than controls. ROI analyses revealed enhanced activation for pediatric-onset MS patients relative to controls in the right middle frontal, left paracingulate, right supramarginal, and left superior parietal gyri during the low executive demand condition, over and above differences in response time. MS patients also demonstrated heightened activation in the right supramarginal gyrus in the high executive demand condition. CONCLUSIONS: Our findings suggest that pediatric-onset MS patients may engage compensatory recruitment strategies during working memory processing. (JINS, 2019, 25, 432-442).

A multi-site, randomized controlled trial of MS INFoRm, a fatigue self-management website for persons with multiple sclerosis: rationale and study protocol.

BACKGROUND: Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS). The majority of approaches for managing MS fatigue typically require participation in a structured, time-limited program with a fixed sequence of topics and activities. MS INFoRm (Multiple Sclerosis: An Interactive Fatigue Management Resource) is a self-directed MS fatigue management resource incorporating principles of self-management and adult learning. Positive results from a feasibility pilot study of a USB-delivered version of MS INFoRm led to the current trial and adaptation of MS INFoRm to a website format. The specific aims of the proposed study are to (a) to determine the effectiveness and efficacy of 3-month use of MS INFoRm on fatigue impact (primary outcome) among persons with MS, (b) to determine whether 3-month use of MS INFoRm results in improvement in secondary outcomes of self- efficacy for managing MS fatigue, self-reported cognitive function, participation and autonomy, and depression, and (c) to determine whether any improvements in primary and secondary outcomes are maintained among the MS INFoRm users after 6-months. METHODS/DESIGN: Parallel group, two arm, double-blinded superiority trial with a 1:1 allocation. Two hundred persons with MS will be randomly assigned to either an intervention (MS INFoRm) or usual care control group in which they will be given 3-month access to either the MS INFoRm website (intervention group) or a control webpage containing widely available resources on MS fatigue (control group). Baseline, immediate post-intervention (3-months), and follow-up (6-months post intervention) evaluations will take place on primary (Modified Fatigue Impact Scale) and secondary (Multiple Sclerosis Self-Efficacy Scale, Perceived Deficits Questionnaire, Center for Epidemiologic Studies Depression Scale, and Impact on Participation and Autonomy Questionnaire) measures. Hypothesis testing will involve independent samples t-tests and mixed effects ANOVAs. DISCUSSION: People with MS may benefit from easily accessible and self-directed fatigue management resources based on self-management and adult learning principles. The proposed study will provide crucial evidence about the potential of MS INFoRm as a self-management tool that can be made widely available to persons with MS as a means to effectively reduce the daily impact of MS fatigue. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03362541 . Posting date December 5, 2017.

Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances.

Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task-based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS.

The Experience of Persons With Multiple Sclerosis Using MS INFoRm: An Interactive Fatigue Management Resource.

We aimed to understand participants' experiences with a self-guided fatigue management resource, Multiple Sclerosis: An Interactive Fatigue Management Resource ( MS INFoRm), and the extent to which they found its contents relevant and useful to their daily lives. We recruited 35 persons with MS experiencing mild to moderate fatigue, provided them with MS INFoRm, and then conducted semistructured interviews 3 weeks and 3 months after they received the resource. Interpretive description guided the analysis process. Findings indicate that participants' experience of using MS INFoRm could be understood as a process of change, influenced by their initial reactions to the resource. They reported experiencing a shift in knowledge, expectations, and behaviors with respect to fatigue self-management. These shifts led to multiple positive outcomes, including increased levels of self-confidence and improved quality of life. These findings suggest that MS INFoRm may have a place in the continuum of fatigue management interventions for people with MS.

Altered resting-state functional connectivity in cognitively preserved pediatric-onset MS patients and relationship to structural damage and cognitive performance.

OBJECTIVE: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. METHODS: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. RESULTS: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex (z=4.21, p<.001), frontal medial cortex (z=3.48, p<.001), and cerebellum (z=3.72, p<.001). Greater T2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region (t=-2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group (p<.05). CONCLUSIONS: Greater resting-state FC between posterior and anterior brain regions is present in pediatric-onset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency.

Mapping two decades of multiple sclerosis rehabilitation trials: A systematic scoping review and call to action to advance the study of race and ethnicity in rehabilitation research.

BACKGROUND: Multiple sclerosis (MS), is prevalent across many racial and ethnic groups, and disproportionately impacts racially minoritized populations. Rehabilitation interventions are an important component of comprehensive MS care. Yet, we do not know the extent to which MS rehabilitation trials consider race and ethnicity in defining eligibility criteria, planning recruitment strategies, selecting outcome measures, supporting intervention delivery, and designing approaches to promote adherence and retention. METHODS: We conducted a scoping review of five databases (MEDLINE, CINAHL, Cochrane Central, EMBASE, and Web of Science) to locate randomized controlled rehabilitation trials published from January 2002 to March 2022. We extracted data from relevant studies, assessed their methodological quality, and narratively summarized results. Reporting of this review is in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). RESULTS: Fifty-six studies of neurorehabilitation (n = 3), cognitive rehabilitation (n = 6), exercise training (n = 9) and self-management (n = 38) interventions were included in this review. The studies were predominantly from North America (n = 44; 73%) or Europe (n = 12; 20%) and included 4280 participants. Most participants (n = 3669; 86%) were Caucasians. Less than 10% of participants were Black (n = 282), Latinx/Hispanic (n = 60), Asian (n = 46), Indigenous (n = 7), or Arab (n = 2). Few studies discussed how race and/or ethnicity were considered in trial planning or execution. CONCLUSIONS: Without consistent and systematic attention to race and ethnicity, both in terms of trial design and reporting, it is impossible to know how MS rehabilitation interventions will translate into real-world applications. This call to action - to the MS rehabilitation research community to ensure trial and intervention processes that accommodate the needs of diverse racial and ethnic groups - is an important first step in addressing inequities in rehabilitation care for persons with MS.

Experiences and perceived outcomes of persons with multiple sclerosis from participating in a randomized controlled trial testing implementation of the Canadian Physical Activity Guidelines for Adults with MS: an embedded qualitative study.

PURPOSE: To describe the experiences and outcomes of participants who enrolled in a randomized controlled trial testing implementation of the Canadian Physical Activity Guidelines for Adults with Multiple Sclerosis. MATERIALS AND METHODS: Fifty-six persons with MS who enrolled in the trial participated in the current study which involved a semi-structured interview at 16-week follow-up. Interview data were analyzed using thematic analysis. RESULTS: Of the 56 participants, 26 ended up enrolling in a community-based exercise program specialized for persons with multiple sclerosis (MS), 7 joined another gym, 4 trained at home, and 17 took part in no specific program. Across all study participants, positive outcomes were reported across a number of domains including mental function, knowledge about the physical activity (PA) and MS, physical function, advocacy of PA to peers, daily participation, and body awareness. For those who enrolled in the community-based program, having a supportive and inclusive environment was critical to their PA experiences. Furthermore, environmental supports, particularly knowledgeable and supportive trainers and similar peers, contributed largely to the positive mental changes and increased knowledge gained. CONCLUSIONS: Our study provides support for the promotion of PA in persons with MS and the development of community-based programs adapted for people with MS.IMPLICATIONS FOR REHABILITATIONEngaging in regular physical activity is associated with many positive benefits and outcomes for people with MS.Supportive elements such as a community of peers who also have MS, adaptive equipment, and trainers who are knowledgeable about MS are especially important for creating positive experiences including enjoyment from and desire to engage in regular physical activity.This study provides support for further advocacy (e.g., by persons with MS directly) and referral to community-based exercise programs adapted for people with MS.

Telephone-based cognitive behavioural therapy for patients with postoperative bariatric surgery to manage COVID-19 pandemic-related mental health issues and distress (TELE-BARICARE): a protocol for a randomised controlled trial.

INTRODUCTION: Bariatric surgery is currently the most effective treatment for obesity, and is performed yearly in over 8000 patients in Canada. Over 50% of those who live with obesity also have a history of mental health disorder. The COVID-19 pandemic has made it difficult for people living with obesity to manage their weight even after undergoing bariatric surgery, which combined with pandemic-related increases in mental health distress, has the potential to adversely impact obesity outcomes such as weight loss and quality of life. Reviews of virtual mental health interventions during COVID-19 have not identified any interventions that specifically address psychological distress or disordered eating in patients with obesity, including those who have had bariatric surgery. METHODS AND ANALYSIS: A randomised controlled trial will be conducted with 140 patients across four Ontario Bariatric Centres of Excellence to examine the efficacy of a telephone-based cognitive behavioural therapy intervention versus a control intervention (online COVID-19 self-help resources) in postoperative bariatric patients experiencing disordered eating and/or psychological distress. Patients will be randomised 1:1 to either group. Changes in the Binge Eating Scale and the Patient Health Questionnaire 9-Item Scale will be examined between groups across time (primary outcomes). Qualitative exit interviews will be conducted, and data will be used to inform future adaptations of the intervention to meet patients' diverse needs during and post-pandemic. ETHICS AND DISSEMINATION: This study has received ethics approvals from the following: Clinical Trials Ontario (3957) and the University Health Network Research Ethics Committee (22-5145), the Board of Record. All participants will provide written informed consent prior to enrolling in the study. Results will be made available to patients with bariatric surgery, the funders, the supporting organisations and other researchers via publication in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05258578.

Self-assessment of cognition in Multiple Sclerosis: the role of personality and anxiety.

OBJECTIVE: : To investigate the role of personality and anxiety to self-report measures of cognition in patients with multiple sclerosis (MS). BACKGROUND: : Self-report measures of cognition have consistently been shown to correlate better with depressed mood than neuropsychological test performance in patients with MS, with few studies focusing on the role of anxiety and personality. METHOD: : One hundred eight MS patients completed the following: (a) patient and informant report Multiple Sclerosis Neuropsychological Questionnaire (MSNQ); (b) Hospital Anxiety and Depression Scale; (c) cognitive assessment with the Brief Repeatable Battery of Neuropsychological Tests; and (d) personality assessment using the self-report NEO Five-Factor Inventory. RESULTS: : Higher patient MSNQ (P-MSNQ) scores (greater reported cognitive dysfunction) were significantly correlated with lower scores on the Paced Auditory Serial Addition Test (PASAT; r=-0.20, P<0.05), increased depression (r=0.45, P<0.01) and anxiety (r=0.54, P<0.01), higher neuroticism (r=0.51, P<0.01), and lower conscientiousness (r=-0.35, P<0.01). After controlling for demographic variables, significant predictors of P-MSNQ scores were anxiety (ΔR=0.272, P<0.001), conscientiousness (ΔR=0.067, P=0.002), and performance on the PASAT (ΔR=0.050, P=0.005). Depression and neuroticism did not contribute significant variance in comparison to anxiety. CONCLUSIONS: : Overall, patient self-reports of cognition did not correspond well to neuropsychological performance. Anxiety and conscientiousness contributed significantly to patients' perceptions of their cognitive failings and thus should be taken into account when addressing these complaints.

A mixed-methods study of cognitive performance in persons with multiple sclerosis: Association between neuropsychological test performance and interviews about daily cognitive functioning.

BACKGROUND: Cognitive difficulties are commonly reported in persons with multiple sclerosis (MS), however, self-reports of cognition often do not correspond well to objective neuropsychological test performance. The use of qualitative interviews can allow for persons with MS to describe in more detail how their cognitive function is impacted in daily life while also taking into consideration personal and environmental influences. No study to our knowledge has examined the association between objective neuropsychological test performance and qualitative interview reports of daily cognitive function. Such information could help explain the reported lack of correspondence between these two methods of evaluating cognitive function in MS. OBJECTIVE: To investigate the relationship between objective neuropsychological test performance and qualitative interview reported daily cognitive function in persons with MS . METHODS: Convergent parallel mixed-methods design whereby 12 persons with MS (mean age= 47, 9 female, 7 relapsing-remitting MS) took part in a 2-hour neuropsychological assessment [including the Brief International Cognitive Assessment for MS (BICAMS)] followed by a semi-structured qualitative interview probing daily cognitive functioning. Interview data were analysed using thematic analysis. Interview codes and themes were compared with neuropsychological performance on respective cognitive domains and between those with and without cognitive impairment on the BICAMS. RESULTS: Based on the qualitative interview data, the most commonly reported difficulties were related to memory, word finding, and processing speed but only 43%, 0%, and 33% of the individuals reporting these deficits actually demonstrated impairment on the respective/ corresponding neuropsychological measures. Eleven of the twelve participants reported the use of strategies to manage cognitive difficulties. The most frequently reported strategies used were related to fatigue management. Personal (age, fatigue) and environmental factors (pressure of daily responsibilities, availability of support) were reported as influencers of daily cognitive function. Three of the 12 participants were classified as cognitively impaired on the BICAMS but they did not differ from those who were non-impaired with respect to use of strategies, and influence of personal and environmental factors on daily cognitive functioning. CONCLUSIONS: Interview-reported daily cognitive difficulties did not correspond well to objective neuropsychological performance. Greater emphasis should be placed on utilizing and developing objective neuropsychological measures that have greater sensitivity, particularly to word finding difficulties in MS, and to the incorporation of personal and environmental factors into the interpretation of neuropsychological test results. As almost all participants reported the use of cognitive strategies, we feel greater emphasis needs to be placed on patient education of evidence-based strategies, particularly focused on highly reported impacted word finding and processing speed abilities.

Validity of an Internet version of the Multiple Sclerosis Neuropsychological Questionnaire.

BACKGROUND: Neuropsychological batteries are long and require expertise to administer. For this reason, the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) was developed as it is quick and easy to complete. The informant version of the scale has proven to be a useful screen for cognitive impairment in multiple sclerosis (MS). OBJECTIVE: The objective was to validate an Internet version of the MSNQ. METHODS: The following psychometric data were collected at home over the Internet in 82 MS patients: (a) patient self-report version MSNQ (P-MSNQ), (b) informant version MSNQ (I-MSNQ), and (c) Center for Epidemiological Studies Depression Scale (CES-D). Thereafter patients underwent in-office testing with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). The sensitivity and specificity of the Internet MSNQ to detect cognitive impairment relative to the BRB-N was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Thirty-five percent of the sample was cognitively impaired. The P-MSNQ was correlated with depression and two tests of the BRB-N. The I-MSNQ was correlated with depression and all five tests of the BRB-N. A cut-off score of 26 on the I-MSNQ gave a sensitivity and specificity of 72% and 60% respectively. Test-retest and internal reliability analyses were strong for both the P-MSNQ and I-MSNQ. CONCLUSION: This is the first attempt at an Internet validation of the MSNQ. The modest sensitivity and specificity values suggest that further research is needed before either the patient or informant version of the MSNQ can be used for neuropsychological screening purposes over the Internet.

Diffusion tensor imaging abnormalities in cognitively impaired multiple sclerosis patients.

BACKGROUND: Cognitive impairment can add to the burden of disease in patients with multiple sclerosis (MS). The aim of this study was to assess the relative importance of diffusion tensor imaging (DTI) indices derived from normal appearing white matter (NAWM) and grey matter (NAGM) in determining cognitive dysfunction in MS patients. METHODS: Sixty two MS patients [51 female, mean age = 41 (sd = 9.6) years, median expanded disability status scale (EDSS) = 2.5] meeting modified McDonald criteria for MS underwent neuropsychological testing using the Neuropsychological Screening Battery for MS (NSBMS) and magnetic resonance imaging (MRI, 1.5T GE) that included DTI sequences. Total T1 hypointense and T2 hyperintense lesion volumes were obtained using semi-automated software. Lesion volumes were subtracted from whole-brain parenchyma to obtain measures of NAWM and NAGM. Fractional anisotropy (FA) of NAWM and mean diffusivity (MD) of NAGM were obtained. RESULTS: Cognitive impairment was present in 11 patients (18%). These patients had higher EDSS scores, were less educated, and were more likely to have secondary progressive MS. They also had higher hypointense (p = 0.001) and hyperintense (p = 0.004) lesion volumes, greater NAWM atrophy (p = 0.007), lower FA of total NAWM (p = 0.003), and higher MD of total NAGM (p = 0.015). Using a logistic regression analysis, and after controlling for demographic and disease-related differences between groups, FA of NAWM emerged as a significant predictor of cognitive impairment adding to the variance derived from lesion and atrophy data. CONCLUSION: This study underlies the important role of normal-appearing brain tissue in the pathogenesis of MS-related cognitive impairment.

The perceptual consequences of the attentional bias: evidence for distractor removal.

A fundamental question of attentional research concerns the perceptual consequences of attention. Spatial attention can enhance stimuli within the focus of attention relative to stimuli outside; or attention can remove the influence of distracting stimuli and other forms of external noise inside the focus of attention. It is known that both strategies apply depending on how attention is cued to a location in space. Here we asked which strategy applies in an uncued situation in which people show a spontaneous bias of attention to the left side. To measure bias, we used a gratingscales task with stimuli corrupted by pixel noise. If biased attention resulted in biased stimulus enhancement its effect should be largest when there is little noise or few distractors within the attended region, and bias should decline with increasing noise. If, however, bias caused distractors to be removed asymmetrically, larger bias should show up with noisy stimuli. We found that bias rose exponentially as noise increased, in agreement with the external noise removal model, and we found evidence that noise modified interhemispheric competition between attentional systems. Our data offer new insights into the neural mechanisms of the right-hemisphere dominance in spatial and attentional tasks.

A pilot mixed-methods evaluation of MS INFoRm: a self-directed fatigue management resource for individuals with multiple sclerosis.

Fatigue management interventions for individuals with multiple sclerosis (MS) often feature structured programmes requiring repeated, in-person attendance that is not possible for all individuals. We sought to determine whether MS INFoRm, a self-directed fatigue management resource for individuals with MS, was worth further, more rigorous evaluation. Our indicators of worthiness were actual use of the resource by participants over 3 months, reductions in fatigue impact and increases in self-efficacy, and participant reports of changes in fatigue management knowledge and behaviours. This was a single-group, mixed-methods, before-after pilot study in individuals with MS reporting mild to moderate fatigue. Thirty-five participants were provided with MS INFoRm by a USB flash drive to use at home for 3 months, on their own volition. Twenty-three participants completed all standardized questionnaires, semi-structured interviews and study process measures. Participants reported actively using MS INFoRm over the 3-month study period (median total time spent using MS INFoRm=315 min) as well as significantly lower overall fatigue impact (Modified Fatigue Impact Scale: t=2.6, P=0.01), increased knowledge of MS fatigue (z=-2.8, P=0.01) and greater confidence in managing MS fatigue (z=-3.3, P=0.001). Individuals with significant reductions in fatigue impact also reported behavioural changes including tracking fatigue, better communication with others, greater awareness, improved quality of life and being more proactive. This study provides evidence that further rigorous evaluation of MS INFoRm, a self-directed resource for managing fatigue, is worth pursuing.

Maturational Trajectory of Processing Speed Performance in Pediatric Multiple Sclerosis.

Processing speed is a frequently affected cognitive domain in pediatric multiple sclerosis (MS) and is commonly assessed using the Symbol Digit Modalities Test (SDMT). The objective of this study was to determine maturational trajectories in SDMT performance and baseline factors affecting trajectories in a sample of 82 pediatric MS individuals. Performance on the SDMT increased with age in patients with pediatric MS followed by a subsequent decline. Furthermore, patients who were older at disease onset and had a higher IQ showed greater gains with age, suggesting that these factors may be protective with respect to cognitive maturation in pediatric MS.

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis.

BACKGROUND: Reduced white matter (WM) integrity is a fundamental aspect of pediatric multiple sclerosis (MS), though relations to resting-state functional MRI (fMRI) connectivity remain unknown. The objective of this study was to relate diffusion-tensor imaging (DTI) measures of WM microstructural integrity to resting-state network (RSN) functional connectivity in pediatric-onset MS to test the hypothesis that abnormalities in RSN reflects changes in structural integrity. METHODS: This study enrolled 19 patients with pediatric-onset MS (mean age = 19, range 13-24 years, 14 female, mean disease duration = 65 months, mean age of disease onset = 13 years) and 16 age- and sex-matched healthy controls (HC). All subjects underwent 3.0T anatomical and functional MRI which included DTI and resting-state acquisitions. DTI processing was performed using Tract-Based Spatial Statistics (TBSS). RSNs were identified using Independent Components Analysis, and a dual regression technique was used to detect between-group differences in the functional connectivity of RSNs. Correlations were investigated between DTI measures and RSN connectivity. RESULTS: Lower fractional anisotropy (FA) was observed in the pediatric-onset MS group compared to HC group within the entire WM skeleton, and particularly the corpus callosum, posterior thalamic radiation, corona radiata and sagittal stratum (all p < .01, corrected). Relative to HCs, MS patients showed higher functional connectivity involving the anterior cingulate cortex and right precuneus of the default-mode network, as well as involving the anterior cingulate cortex and left middle frontal gyrus of the frontoparietal network (all p < .005 uncorrected, k≥30 voxels). Higher functional connectivity of the right precuneus within the default-mode network was associated with lower FA of the entire WM skeleton (r = -.525, p = .02), genu of the corpus callosum (r = -.553, p = .014), and left (r = -.467, p = .044) and right (r = -.615, p = .005) sagittal stratum. CONCLUSIONS: Loss of WM microstructural integrity is associated with increased resting-state functional connectivity in pediatric MS, which may reflect a diffuse and potentially compensatory activation early in MS.

Brain activation patterns and cognitive processing speed in patients with pediatric-onset multiple sclerosis.

OBJECTIVE: This study aimed to determine the extent and pattern of brain activation elicited by a functional magnetic resonance imaging version of the Symbol Digit Modalities Test (fMRI-SDMT), a task of information processing speed, in pediatric-onset multiple sclerosis (MS) patients as compared to sex- and age-matched non-MS self-reported healthy individuals. METHOD: Participants included 20 right-handed individuals aged 13-24 years with pediatric-onset MS (mean age = 19 years, 15 female) and 16 non-MS self-reported healthy individuals. All participants underwent a 3.0-tesla MRI scan with structural (T1; T2; proton density, PD; fluid-attenuated inversion recovery, FLAIR) and fMRI-SDMT acquisition. Participants were instructed to indicate with a button press whether a single pairing of a symbol to a number matched any of those shown in a key that displays nine possible pairings. RESULTS: Response time (p = .909) and accuracy (p = .832) on the fMRI-SDMT did not differ between groups. However, the MS group demonstrated lower overall activation than the non-MS group in the right middle frontal gyrus (p = .003). Within the MS group, faster response time was associated with greater activation of the right inferior occipital, anterior cingulate, right superior parietal, thalamus, and left superior occipital cortices (all p < .05). A significant interaction effect was demonstrated, indicating that faster response time was associated with greater activation of the left superior occipital region in the pediatric MS group than in the non-MS group (p = .002). CONCLUSIONS: Attenuated activation of frontal regions was observed in this cohort of pediatric-onset MS patients when performing the fMRI-SDMT, even in the absence of behaviorally detectable deficits. Within the MS group only, faster response time elicited greater activation, suggesting this to be an adaptive mechanism that may contribute to limiting the impact of disease-related structural pathology.

Predicting employment status in multiple sclerosis patients: the utility of the MS functional composite.

As many as two-thirds of multiple sclerosis (MS) patients are unable to retain employment. Neurological and cognitive status are known to be significant predictors of unemployment, but the relationship between the two is unclear. Furthermore, the association between employment status and depression, anxiety, and personality has not been adequately explored in MS patients. This study examined the demographic, neurological, neuropsychological, and personality factors associated with unemployment in MS. We also sought to determine the utility of the Multiple Sclerosis Functional Composite (MSFC), a measure of MS-related disability incorporating physical and cognitive measures, in predicting employment status. A consecutive sample of 106 MS patients (61.3% unemployed) completed the Brief Repeatable Battery of Neuropsychological Tests (BRBN), Hospital Anxiety and Depression Scale (HADS), and NEO Five-Factor Personality Inventory. The MSFC emerged as the most robust predictor of employment status in MS patients, exceeding the predictive value of the EDSS. Together with NEO "Agreeableness" and HADS Depression subscore, the MSFC accounted for 49.8% of the variance in employment status. Unemployment was also associated with a progressive disease course, longer disease duration, and being female. While Global Cognitive Impairment did not differentiate between groups, unemployed patients scored significantly lower on three of five BRBN indices: Symbol Digit Modality Test, Paced Auditory Serial Addition Test, and Word List Generation. The findings highlight the utility of the MSFC as a predictor of unemployment in MS. Furthermore, a strong association was found between unemployment and the personality construct "Agreeableness", and severity of depression.

Validity of a computerized version of the symbol digit modalities test in multiple sclerosis.

The Symbol Digit Modalities Test (SDMT) is a particularly sensitive measure of cognitive dysfunction in patients with multiple sclerosis (MS). While computerized versions have been developed for use in functional magnetic resonance imaging (fMRI), none has been validated in MS patients. The aim of this study was to validate a new computerized version of the SDMT for use in MS patients. We developed a novel computerized version of the SDMT (c-SDMT) which was completed by 119 MS patients and 38 healthy controls. Our version consisted of eight timed trials of nine symbols. Both groups also underwent cognitive testing with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) which included the 90-s paper SDMT (p-SDMT) scored according to the number of correct responses per each 15-s interval. The sensitivity and specificity of the c-SDMT and p-SDMT to detect overall cognitive impairment on the BRB-N was determined. MS patients performed significantly worse than controls on both the c-SDMT (t = -6.1, p < 0.001) and p-SDMT (t = 5.7, p < 0.001). More MS patients were impaired on the c-SDMT than the p-SDMT (37% vs. 29%). The sensitivity and specificity of the SDMT was as follows: 71% and 84%, respectively, for the c-SDMT, and 67% and 95%, respectively, for the p-SDMT. Both versions detected a significant group × time effect over the course of the individual trials, although the pattern of responses differed between them. Good test-retest reliability for the c-SDMT was shown (ICC = 0.94). The results support the validity of this version of the c-SDMT as a sensitive measure of cognitive dysfunction in MS. The methodology is also fMRI compatible.